President Biden of the United States (US) has recently signed into law the Fiscal Year 2023 Omnibus Appropriations Bill, which included the FDA Modernization Act 2.0. This act amends the Federal Food, Drug, and Cosmetic Act (FFDCA), which applies to new drugs, and the Public Health Service Act, which applies to biosimilars. As a result, the FDA is now required to consider alternatives to animal testing, such as in vitro, in silico, and in chemico tests and models.

Opinions regarding how the new act will impact the industry vary, with predictions ranging from everything remaining at the status quo to the end of animal testing for new drug development and approvals. In the end, time will tell how the FDA implements the changes into actual practice. Given the difficulty of modeling complex biological systems using only in vitro and in silico techniques, it is unlikely that animal testing will be eliminated for all new drug applications. However, the FDA had approved New Drug Applications (NDAs) without new animal studies even prior to the new act and embraces the use of innovative and flexible approaches for new drug approvals.

In this blog post, we examine several alternative approaches to animal testing and how the FDA handles the application of these methods in specific scenarios.

The 505(b)(2) NDA Pathway

Drug development via the 505(b)(2) regulatory pathway often allows for a reduction or even elimination of animal testing required to open an Investigational New Drug application (IND) and for NDA approval. In the US, new small molecule drugs are developed under the requirements of Sections 505(b)(1) and 505(b)(2) of the FFDCA. A 505(b)(2) NDA leverages information from studies in the literature and/or approved labeling for another drug that the sponsor does not own or have right of reference to. This strategy can reduce the overall study requirements for approval.[1] The following are two examples of new drugs that were approved without new animal studies:

Unithroid® [2]

Prior to 1997, Unithroid® (levothyroxine sodium oral tablets) and similar levothyroxine sodium products (e.g., Synthroid® oral tablets) were marketed as unapproved drugs for the treatment of hypothyroidism in the US. Due to concerns over manufacturing consistency and stability, the FDA required all oral levothyroxine manufacturers to obtain NDAs to continue marketing their products lawfully. The Unithroid® NDA leveraged its long history of clinical use and published literature to support the safety of Unithroid®, and no new animal studies were required for the approval of its 505(b)(2) NDA on 8/21/2000.

Loreev XR® [3]

Loreev XR® (lorazepam – extended-release oral capsules) is a benzodiazepine indicated for the treatment of anxiety that offers once daily dosing, contrasted with the two to three times per day dosing for the immediate-release versions of lorazepam such as Ativan® oral tablets. The Loreev XR® formulation used excipients commonly used in other oral drug products, and all impurities were within ICH Q3A and Q3B specifications. A scientific bridge was established between Loreev XR® and Ativan®, allowing the Ativan® safety information to be used to support the safety of Loreev XR®, and therefore no new animal studies were required for the approval of its 505(b)(2) NDA on 8/27/2021.

Mutagenic Impurity Analysis Using QSAR

In accordance with the ICH M7 guidance on mutagenic impurities, the FDA routinely utilizes quantitative structure-activity relationship (QSAR) models to predict the mutagenic potential of impurities in drug substances. The approach outlined in the guidance can lead to a conclusion that no further in vitro or in vivo (animal) testing is needed.[4]

In Vitro Assessments

The FDA uses various in vitro assessments to evaluate the safety of new drug products. For example, the ICH S10 photosafety guidance calls for the use of a tiered testing process whereby the ultraviolet and visible absorption of a drug product is evaluated to determine if additional testing is required.[5] If it is, in vitro phototoxicity assessments are conducted, and, if there is no indication of phototoxicity potential, no additional work (including animal studies) is required.

Similarly, for new topical dermal products, the FDA requires ocular safety assessments but encourages the use of in vitro or ex vivo methods instead of animal studies.[6]

Weight-of-Evidence Assessments

Sponsors will likely also have additional opportunities to leverage alternatives to animal models, such as in silico models, to predict the carcinogenicity of a chronically-administered drug. These predictions can then be used as part of a weight-of-evidence approach, such as that outlined in the recently revised ICH S1B guidance on carcinogenicity testing. In this way, a program can potentially be reduced to a single-species carcinogenicity study, or animal testing may be waived altogether.[7]

Clinical Implications

Although the changes implemented by the FDA Modernization Act 2.0 are focused on reducing animal testing, this new openness to applying alternative models may also flow over to clinical programs. In silico population pharmacokinetic (popPK) and physiologically-based pharmacokinetic (PBPK) modeling can reduce or eliminate certain clinical studies, as was done with the 505(b)(2) approval of the long-acting injectable Aristada® (aripiprazole lauroxil).[8]

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Premier Consulting helps sponsors leverage alternative models and regulatory pathways to move their products quickly into the clinic. We continually work to leverage novel approaches to reduce testing requirements (both nonclinical and clinical), embrace the 3Rs of animal welfare (replacement, reduction, and refinement), and speed product development. Contact us to learn more about how our nonclinical strategy and execution experts can move your program toward its next milestone.

Authors:

William Salminen, PhD, DABT, PMP
Vice President, Nonclinical Safety and Toxicology

Madelyn “Mimi” Huang, PhD, DABT
Toxicologist

References:

[1] US Food and Drug Administration (FDA) Center for Drug Evaluation and Research (CDER). Applications covered by Section 505(b)(2) – draft guidance for industry. 1999.

[2] US Food and Drug Administration (FDA). Summary basis of approval (SBA) for Unithroid (NDA 21210, 8/21/2000), https://www.accessdata.fda.gov/drugsatfda_docs/nda/2000/21210_Unithroid.cfm [accessed 23 March 2023].

[3] US Food and Drug Administration (FDA). Summary basis of approval (SBA) for Loreev XR (NDA 214826, 8/27/2021), https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/214826Orig1s000TOC.cfm [accessed 23 March 2023].

[4] International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). ICH Harmonised Guideline M7(R1): Assessment and control of DNA reactive (mutagenic) impurities in pharmaceuticals to limit potential carcinogenic risk. 2017.

[5] International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). ICH Harmonised Guideline S10: Photosafety evaluation of pharmaceuticals. 2013.

[6] US Food and Drug Administration (FDA) Center for Drug Evaluation and Research (CDER). Nonclinical safety evaluation of reformulated drug products and products intended for administration by an alternate route. 2015.

[7] International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). ICH Harmonised Guideline S1B(R1): Testing for carcinogenicity of pharmaceuticals. 2022.

[8] US Food and Drug Administration (FDA). Summary basis of approval (SBA) for Aristada (NDA 207533, 10/5/2015), https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=207533 [accessed 23 March 2023].